key: cord-0767559-icnvlt0b
authors: Rasmussen, Bodil S.; Klitgaard, Thomas L.; Perner, Anders; Brand, Björn A.; Hildebrandt, Thomas; Siegemund, Martin; Hollinger, Alexa; Aagaard, Søren R.; Bestle, Morten H.; Marcussen, Klaus V.; Brøchner, Anne C.; Sølling, Christoffer G.; Poulsen, Lone M.; Laake, Jon H.; Aslam, Tayyba N.; Bäcklund, Minna; Okkonen, Marjatta; Morgan, Matthew; Sharman, Mike; Lange, Theis; Wetterslev, Jørn; Schjørring, Olav L.
title: Oxygenation targets in ICU patients with COVID‐19: A post hoc subgroup analysis of the HOT‐ICU trial
date: 2021-09-20
journal: Acta Anaesthesiol Scand
DOI: 10.1111/aas.13977
sha: 1dab25c34ba6f19ea208656c459932fae9f72c25
doc_id: 767559
cord_uid: icnvlt0b

BACKGROUND: Supplemental oxygen is the key intervention for severe and critical COVID‐19 patients. With the unstable supplies of oxygen in many countries, it is important to define the lowest safe dosage. METHODS: In spring 2020, 110 COVID‐19 patients were enrolled as part of the Handling Oxygenation Targets in the ICU trial (HOT‐ICU). Patients were allocated within 12 h of ICU admission. Oxygen therapy was titrated to a partial pressure of arterial oxygen (PaO(2)) of 8 kPa (lower oxygenation group) or a PaO(2) of 12 kPa (higher oxygenation group) during ICU stay up to 90 days. We report key outcomes at 90 days for the subgroup of COVID‐19 patients. RESULTS: At 90 days, 22 of 54 patients (40.7%) in the lower oxygenation group and 23 of 55 patients (41.8%) in the higher oxygenation group had died (adjusted risk ratio: 0.87; 95% confidence interval, 0.58–1.32). The percentage of days alive without life support was significantly higher in the lower oxygenation group (p = 0.03). The numbers of severe ischemic events were low with no difference between the two groups. Proning and inhaled vasodilators were used more frequently, and the positive end‐expiratory pressure was higher in the higher oxygenation group. Tests for interactions with the results of the remaining HOT‐ICU population were insignificant. CONCLUSIONS: Targeting a PaO(2) of 8 kPa may be beneficial in ICU patients with COVID‐19. These results come with uncertainty due to the low number of patients in this unplanned subgroup analysis, and insignificant tests for interaction with the main HOT‐ICU trial. Trial registration number: ClinicalTrials.gov number, NCT03174002. Date of registration: June 2, 2017.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic. The virus causes coronavirus disease 2019 (COVID-19) ranging in severity from fever and mild upper respiratory tract symptoms to acute respiratory distress syndrome (ARDS) with severe hypoxemia requiring advanced respiratory support in the intensive care unit (ICU). Worldwide, the mortality of patients admitted to the ICU with COVID-19 is high, being close to 40%. 1 Supplemental oxygen is the key component of supportive care, but the balance between benefits and harms of different oxygenation targets is unknown for ICU patients with COVID- 19. 2 In ICU patients with ARDS by any etiology, clinical practice guidelines give no recommendation for oxygenation targets. 3, 4 One oxygenation target that is often referred to as a partial pressure of arterial oxygen (PaO 2 ) between 7.3 and 10.7 kPa or a SpO 2 of 88 and 95% defined as a standard of care in randomized trials performed by the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. 5--7 A recent trial, Liberal or Conservative Oxygen Therapy (LOCO 2 ), in ARDS patients of a similar low target (PaO 2 , 7.3 to 9.3 kPa or SpO 2 , 88% to 92%) versus a higher target (PaO 2 , 12 to 14 kPa or SpO 2 above 95%) was stopped prematurely because 5 of 99 patients had mesenteric ischemia in the lower oxygenation group as compared to none of 102 patients in the higher oxygenation group, and likewise a significant difference in 90-day mortality between the two groups was found. 8 In the Handling Oxygenation Targets in the ICU (HOT-ICU) trial, we found no difference in the number of ischemic events nor in 90-day mortality among 2928 patients with moderate to severe acute hypoxaemic respiratory failure acutely admitted to the ICU comparing similar lower and higher oxygenation targets. 9 Also, no differences in mortality at 90 or 180 days were found in the Intensive Care Unit Randomized Trial Comparing Two Approaches to Oxygen Therapy (ICU-ROX) in which 1000 invasively mechanically ventilated patients were enrolled. 10 During the first wave of the COVID-19 pandemic, 110 ICU patients with COVID-19 were enrolled in the HOT-ICU trial. 9 The HOT-ICU trial was completed on August 3, 2020, and the primary results have been published. 9 With the unstable supplies of medical oxygen in many countries and the lack of evidence in this area, we find it important to report key outcomes at 90 days for the subgroup of COVID-19 patients enrolled in the HOT-ICU trial.

Twelve HOT-ICU trial sites in Denmark, Switzerland, Norway, Finland, and the United Kingdom enrolled one or more patients with documented positive SARS-CoV-2 test at baseline or during Results: At 90 days, 22 of 54 patients (40.7%) in the lower oxygenation group and 23 of 55 patients (41.8%) in the higher oxygenation group had died (adjusted risk ratio: 0.87; 95% confidence interval, 0.58-1.32). The percentage of days alive without life support was significantly higher in the lower oxygenation group (p = 0.03). The numbers of severe ischemic events were low with no difference between the two groups.

Proning and inhaled vasodilators were used more frequently, and the positive endexpiratory pressure was higher in the higher oxygenation group. Tests for interactions with the results of the remaining HOT-ICU population were insignificant.

Conclusions: Targeting a PaO 2 of 8 kPa may be beneficial in ICU patients with COVID-19.

These results come with uncertainty due to the low number of patients in this unplanned subgroup analysis, and insignificant tests for interaction with the main HOT-ICU trial.

Trial registration number: ClinicalTrials.gov number, NCT03174002.

Date of registration: June 2, 2017.

intensive care units, oxygen inhalation therapy, randomized controlled trial, respiratory insufficiency, severe acute respiratory syndrome coronavirus 2

In this substudy of the HOT-ICU randomized controlled trial the ICU stay. Written informed consent was obtained from the patients or their legal surrogate as per the relevant legislation. The HOT-ICU trial was registered at ClinicalTrials.gov (NCT03174002) before the enrolment of the first patient. The protocol and statistical analysis plan were published before enrolment was completed. 11, 12 The HOT-ICU trial was an investigator-initiated, multicenter, stratified, parallel-grouped, randomized clinical trial with 35 participating ICUs in Denmark, Switzerland, Norway, Finland, the United Kingdom, the Netherlands, and Iceland. The 

We screened patients aged 18 years or above who were acutely admitted to the ICU, received at least 10 L of oxygen per minute in an open system or at least a fraction of inspired oxygen (FiO 2 ) of 0.50 in a closed system, had an arterial line, and were expected to receive supplemental oxygen therapy for at least 24 h in the ICU.

We excluded patients that could not be randomized within 12 h of ICU admission; all exclusion criteria are provided in the Supporting Information. In the present subgroup analysis of the HOT-ICU trial, we only include patients who had at least one airway sample positive for SARS-CoV-2 by PCR analysis at randomization or at any time during the ICU admission.

Patients were randomly assigned to oxygen therapy titrated to achieve a PaO 2 of 8 kPa (lower oxygenation group) or a PaO 2 of 12 kPa (higher oxygenation group) during the entire ICU stay, including re-admissions, to a maximum of 90 days after randomization. To document the intervention, we registered the lowest and the highest PaO 2 in predefined 12-hour intervals with concomitant values for arterial oxygen saturation (SaO 2 ) and FiO 2 . All patients were continuously monitored with SpO 2 to maintain the assigned PaO 2 . The oxygenation targets were achieved by adjustments of the FiO 2 . All other interventions in the ICU were at the discretion of the clinicians.

We present key outcomes at 90 days as predefined in the HOT-ICU trial including; all-cause mortality; percentage of days alive without the use of life support defined as invasive or non-invasive mechanical ventilation or continuous positive airway pressure treatment, vasopressor or inotropic therapy, or renal replacement therapy; percentage of days alive and out of hospital; and the number of patients with one or more serious adverse events defined as new episodes of shock, myocardial ischemia, intestinal ischemia, or ischemic stroke in the ICU within 90 days, details are provided in the Supporting Information.

We did no sample size estimation for the analyses reported here.

All analyses were conducted according to the intention-to-treat principle 13 and according to the statistical analysis plan for the HOT-ICU trial. 12 The intention-to-treat population included all randomized patients positive for SARS-CoV-2 in the HOT-ICU trial except for those where follow-up data could not be obtained due to the withdrawal of consent according to national regulations. [14] [15] [16] We compared 90-day mortality in the two groups using a generalized linear model with a log-link and a binomial error distribution adjusted for the stratification variables site and COPD, but not for active hematological malignancy due to non-convergence in the model. Results are presented as RR and risk differences (RD) with corresponding 95% CI. We also performed a secondary analysis of mortality adjusted for all stratification variables and for baseline parameters; age, presence or absence of active metastatic cancer, type of admission (medical, elective surgical or emergency surgical), and sequential organ failure assessment (SOFA) score calculated on the basis of six organ systems (respiration, coagulation, liver, cardiovascular, central nervous system, and renal) with higher scores indicating more severe organ dysfunction and a maximum score of 24, 17 using a logistic regression model presented as odds ratio with 95% CI. We compared survival times using Kaplan-Meyer curves sup- (Table 1 ).

During the 90 days of intervention in the ICU, the daily medians of the registered PaO 2 and the corresponding FiO 2 and SaO 2 were lower in the lower oxygenation group as compared to the higher oxygenation group (Figure 2 ). The patient numbers in the figures are provided in the Supporting Information, as well as the highest and lowest registered PaO 2 with corresponding FiO 2 and SaO 2 (Table S1; Figure S1 -S3). Details on the process of care in the ICU for the two oxygenation groups are provided in Table 2 . (Table 2; Table S3 ). The corresponding days alive without life-support were 57.5 and 61.0, respectively (Table S2) . A histogram of percentages of days alive out of hospital in the two oxygenation groups are provided in the Supporting Information ( Figure S4 ). No significant differences between the two groups were found in the percentage of days alive and out of the hospital or in the number of patients with one or more serious adverse events ( Table 2; Table S4 ). . IQR are missing for some points as there is only one measurement for these particular days, see Table S1 in the supplement for patient numbers by days. SaO 2 values were not available in blood gas analyses from one site and were therefore missing for 19 patients Note: Data are presented as median (IQR) or n (%), as appropriate.

Abbreviations: CPAP, continuous positive airway pressure; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; IQR, interquartile range; MV, mechanical ventilation; NIV, non-invasive ventilation; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure.

*The seemingly large difference in the two-point estimates is due to a zero-inflated negatively skewed distribution (the histograms are provided in the Supporting Information).

not blinded, and data of specific medical treatments for COVID-19

were collected. Also, targeting higher oxygenation may make interventions more likely to occur to achieve this, thus if there is harm in the higher oxygenation group, it may result from the interventions to achieve this and not from the oxygen itself.

In conclusion, in this post hoc subgroup analysis of ICU patients with COVID-19 enrolled in the HOT-ICU trial, a lower oxygenation target did not result in a statistically significant reduction in mortality as compared to higher oxygenation target. With the depleted oxygen resources in the part of the world, our data may justify the present recommendation with a SpO 2 target up to a maximum of 96% until more solid evidence is obtained.

We wish to thank patients, relatives, clinical staff, and research staff at all trial sites during the challenging first wave of the COVID-19

pandemic. Without their support, COVID-19 patients would never have been included in the HOT-ICU trial. 

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The authors report no conflicts of interest.